The present invention relates to powders with electrostatic properties as well as a process and a method for preparation of such an electro-powder as a s medical powder and more particularly to preparations of chemical and biological substances forming an electro-powder suitable for electrostatic charging and dosing for functionality in an inhaler device.
Today high quality dosing is one of the most difficult factors slowing down the growth of the inhaler market. This is specially the case for systemic delivery by inhalation through a dry powder inhaler (DPI) which represents a market segment making it possible to compete with the injection needle for many types of drugs, i.e. insulin, pain management etc. Systemic delivery refers to the delivery of an active substance to be carried to a deep area of the lung. U.S. Pat. No. 5,997,848 discloses a systemic delivery of insulin to a mammalian host being accomplished by inhalation of a dry powder of insulin. An insulin dose 0.5 to 15 mg is dispersed into a high velocity air or gas stream to form a dry insulin aerosol in a holding chamber from which the created aerosol is inhaled. The volume of the chamber has to be sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. Such a device is often referred to as a spacer. The device for instance has a drawback in that there are difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder will stick to the walls of the spacer.
A dry powder inhaler, DPI is intended for administration of powder into the deep or upper lung airways by oral inhalation. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place. Particle sizes, to reach into the deep lung, should be in the range 0.5-3 xcexcm and for a local lung delivery in the range 3-5 xcexcm, as measured with a laser diffraction instrument, e.g. a Malvern Mastersizer for physical size classification or an Andersen Impactor for an aerodynamic size classification according to US Food and Drug Administration (FDA) current guidelines.
Powders for inhalers have a tendency of agglomerating, in other word to clod or to form small or larger lumps, which then have to be de-agglomerated. De-agglomeration is defined as breaking up agglomerated powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a step one during dosing and as a final step two during the patient""s inspiration through the DPI.
Technologies to de-agglomerate today include advanced mechanical and aerodynamic systems and combinations between electrical and mechanical filling systems that can be seen in for instance in U.S. Pat. No. 5,826,633. Further there are systems disclosed for dispersing aerosolized doses of medicaments, e.g. U.S. Pat. No. 5,775,320, U.S. Pat. No. 5,785,049, and U.S. Pat. No. 5,740,794. Furthermore, in our International Publications WO 00/0636 and WO 00/6235 principles for de-agglomeration and classification are disclosed.
As already noted for an optimal amount of substance to reach the alveoli, an administered powder dose should preferably have a grain size between 0.5 and 3 xcexcm. Besides, the inspiration must take place in a calm way to decrease air speed and thereby reduce deposition in the upper respiratory tracts.
Mainly particles larger than 5 xcexcm will be deposited in the upper airways by impaction and particles less than 0.5 xcexcm will not sediment before exhaling and therefore not being efficient for delivery to upper or deep lung.
It is also common to utilize carriers i.e. Lactose having a larger grain size onto which the fine power is distributed. Upon inspiration the large size grains will then stick in the oral cavity while the fine particle fraction, this is powder smaller than 5 xcexcm, will be let free and proceed to the lung. For instance U.S. Pat. No. 5,642,727 discloses a tribo-inhaler having a container portion for electrostatically retaining a predefined dose of medicament powder. The container portion contains a plurality of polymeric beads that have diameters of approximately 50 to 200 microns. Each of the polymeric beads has a specific quantity of dry powder medicament electrostatically adhered to its surface.
To achieve a high quality dose, a so-called spacer is often used to achieve the small grains evenly distributed in a container from which the inhalation can take place. In principal a dosing device or an inhaler is connected to a spacer forming a container having a relatively large volume and into this container a powder or an aerosol is injected, which partly is distributed in the air space and partly sticks to the walls. Upon inhalation from the spacer the fine powder floating free in the air will effectively reach the alveoli of the lung. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus. The uncontrolled sticking to the walls is highly dependent on the electrostatic charge of the medical powder.
Today dosing into cavities for inhalation through a dry powder inhaler (DPI) is performed by using mechanical, fluidization and electrical technologies in combinations to fill cavities with powder intended for inhalation by patients. One example of this technique is the already mentioned U.S. Pat. No. 5,826,633 in which a combination of fluidization and mechanical forces is used to fill a cavity with a metered dose.
This type of technique will give a dose that will need a lot of energy to de-agglomerate before inhalation into the deep lung. This is performed using a mechanical pump that is actuated before inhalation and a high-pressurized air stream is shot down into the powder for de-agglomeration into a cylindrical spacer. Inhalation efficiency for this type of system is normally not more than 20% of metered dose.
One major problem with some of the technique described above is to also obtain a low relative standard deviation (RSD) between doses with this type of technique due to lack of in-line control possibilities in production making it hard to be in compliance with regulatory demands.
Different commercial manufacturing equipment are today present on the market, i.e. equipment used to produce micronized powders working with specialized nozzles for creating liquid or semisolid aerosols, which are dried to powders. The equipment can also be used for coating-techniques and Cryo-techniques to produce low-density powders. Fluid Jet Mill equipment is used to produce micronized powders by working with high-pressurized gases, normally air or nitrogen. Also solvents defined as liquids are used to dissolve or disperse active substances and excipients, e.g. alcohols, before sprayed into the manufacturing equipment or other gases such as carbon dioxide, chlorofluorocarbons or eqivalent, perfluorocarbons, air or other suitable inert gas for the manufacturing equipment can be used. Such equipment also can be used for purposes of coating, drying and Cryo-techniques, one at a time or in combinations, where Cryo-techniques is a method in which super cold media, i.e. liquid nitrogen or carbon dioxide, is used for cooling down the manufacturing equipment and the preparation below 0xc2x0 C. Blending is defined as a homogeneous mixture of at least one active substance and one or many excipients regardless of amounts and particle sizes, and can be used alone or in combinations with spray drying and Fluid Jet Milling to prepare an electro-powder. By the term excipient is meant a chemical or biological substance introduced together with a pharmaceutical active substance to, for instance, improve the performance of the preparation or is an compound intended to act as an inactive surface and/or volume suitable for the active substance normally being a mix preferably chosen among the available excipients not to deteriorate the powder properties of the preparation.
Micronized medical powders are being electrostatically charged in many occasions in the pharmaceutical industry whereby this creates a big problem by causing stops and producing dust on surfaces that should be kept clean.
When electrostatic properties of a micronized medical powder is controlled this can be used to present an efficient and high quality dosing from electrostatically operating equipment such as disclosed in our U.S. Pat. No. 6,089,227 as well as our Swedish Patents No. 9802648-7 and 9802649-5, which present excellent inhalation dosing performance.
An International Publication WO 00/35424 discloses a substrate coating for electrostatic deposition of dry powder medicaments for use in the manufacture of pharmaceutical dosage forms. The dry powder comprises micronized polyethylene glycol (PEG), with a molecular weight of 1,000 to 20,000. However, the particles are stated to have a size of 1-100 xcexcm and a preferred size is claimed for 5-20 xcexcm but there is nothing told about the fine particle fraction or the specific charge of a fine particle fraction.
However, there is still a need for a much more developed control of the electrostatic charging quality of applicable medical powders before they are going to be used in electrostatic dosing equipment.
The present invention makes it possible for a majority of dry medical substances to be prepared by using the method and process of the present invention to obtain a medical dry powder, xe2x80x9celectro-powderxe2x80x9d, suitable for electrostatic charging and dosing. The electro-powder thus obtained will be possible to dose with high efficiency and quality by electrostatic dosing equipment.
A method and a process for preparation of medical powders for electrostatic charging are disclosed. An electro-powder results from preparations of chemical and biological substances to form powders suitable for electrostatic charging and dosing for functionality in a dry powder inhaler device. The electro-powder resulting from the method and process forms an active dry powder substance or dry powder medical formulation with a fine particle fraction (FPF) representing of the order 50% or more of the content ranging between 0.5-5 xcexcm and provides electrostatic properties with an absolute specific charge per mass after charging of the order 0.1 to 25 xcexcC/g and presents a charge decay rate constant Q50 of more than 0.1 s, and having a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5. In the processing the active substance is generally a pharmaceutical active chemical or biological substance, for instance a polyeptide, or any other corresponding substance selected alone or mixed or blended together with one or more excipients being a compound to improve electrostatic properties of the medical powder substance or dry powder medical formulation. Further the electro-powder may even be formed as a micro-encapsulation by coating micronized powder with the excipient in such a way that the active substance is capsulated, whereby the powder electrostatic properties mainly comes from the excipient.
A method for producing electro-powder according to the present invention is set forth by the independent claim 1 and further embodiments are set forth by the dependent claims 2 to 7, a process for acquiring the electro-powder is set forth by the independent claim 8 and further embodiments of the process are set forth by the dependent claims 9 to 23. Finally an electro-powder according to the present invention for use with a dry powder inhaler is set forth by the independent claim 24 and the dependent claims 25 to 40.